Pharmacokinetics of intravenous amiodarone and its electrocardiographic effects on healthy Japanese subjects

• Published in: Heart and vessels Vol. 26; no. 3; pp. 274 - 281
• Main Authors: Shiga, Tsuyoshi, Tanaka, Takanori, Irie, Shin, Hagiwara, Nobuhisa, Kasanuki, Hiroshi
• Format: Journal Article
• Language: English
• Published: Japan Springer Japan 01.05.2011; Springer Nature B.V
• Subjects: Adult; Amiodarone - administration & dosage; Amiodarone - adverse effects; Amiodarone - analogs & derivatives; Amiodarone - blood; Amiodarone - pharmacokinetics; Anti-Arrhythmia Agents - administration & dosage; Anti-Arrhythmia Agents - adverse effects; Anti-Arrhythmia Agents - blood; Anti-Arrhythmia Agents - pharmacokinetics; Area Under Curve; Asian Continental Ancestry Group; Biomedical Engineering and Bioengineering; Biotransformation; Blood Pressure - drug effects; Cardiac arrhythmia; Cardiac Surgery; Cardiology; Computer Simulation; Drugs; Electrocardiography; Electrocardiography, Ambulatory; Half-Life; Heart Rate - drug effects; Humans; Infusions, Intravenous; Japan; Male; Medicine; Medicine & Public Health; Models, Biological; Original Article; Pharmacology; Vascular Surgery; Young Adult; Japan; Healthy subjects; Amiodarone; Pharmacokinetics; Desethylamiodarone
• ISSN: 0910-8327; 1615-2573; 1615-2573
• DOI: 10.1007/s00380-010-0047-7

The aim of this phase I, dose-escalating study was to evaluate the pharmacokinetics, electrocardiographic effect and safety of amiodarone after a single intravenous administration in Japanese subjects. Thirty-two healthy Japanese male volunteers (20–32 years) were randomized to three single-dose groups (1.25, 2.5 and 5.0 mg/kg). In each group, six (1.25 mg/kg) or ten (2.5 and 5.0 mg/kg) subjects received a single 15-min infusion of intravenous amiodarone, and two subjects received glucose solution as control. The pharmacokinetic profile, blood pressure and electrocardiographic analyses were obtained on a timely basis after up to 77 days. The maximum plasma concentration ( C max ) and area under the concentration-time curve (AUC 0–96 ) for amiodarone 1.25, 2.5 and 5.0 mg/kg displayed dose-dependent characteristics: mean C max was 2,920 ± 610, 7,140 ± 1,480 and 13,660 ± 3,410 ng/ml, respectively; the mean AUC 0-96 was 3,600 ± 700, 8,100 ± 1,600 and 16,600 ± 4,300 ng h/ml, respectively. A long serum half-life (>14 days) was observed for amiodarone and desethylamiodarone. PR intervals were prolonged at 15 min (0.16 ± 0.0.1 vs. 0.15 ± 0.01 s, p  = 0.03) and 18 min (0.17 ± 0.01 vs. 0.15 ± 0.01 s, p  = 0.03) with the 5.0 mg/kg dose compared with baseline. No other significant changes in electrocardiographic parameters, pulse rate or blood pressure were observed. A needle-pain-induced vasovagal effect appeared in a volunteer, and three volunteers experienced pain at the drug infusion site. After a single infusion of amiodarone at doses of 1.25–5.0 mg/kg, serum concentrations increased in a dose-dependent manner. A single intravenous amiodarone dose barely affected the electrocardiographic parameters and was well tolerated.